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{{Short description|Typical antipsychotic medication}}
{{distinguish|Thorazine}}
{{Redirect|Aldazine|functional group|Aldazines}}
{{drugbox | Verifiedfields = changed
{{Distinguish|Thorazine}}
| Watchedfields = changed
{{Lead too short|date=September 2021}}
| verifiedrevid = 416502199
{{Use dmy dates|date=July 2020}}
| IUPAC_name = 10-{2-ethyl}-<BR>2-methylsulfanylphenothiazine
{{Infobox drug
| image = Thioridazine-2D-skeletal.png
| verifiedrevid = 470608946
| width = 175
| IUPAC_name = 10-{2-ethyl}-<br />2-methylsulfanylphenothiazine
| image2 = Thioridazine3d.png
| image = Thioridazine.svg
| width = 200px


<!--Clinical data--> <!--Clinical data-->
| Drugs.com = {{drugs.com|CDI|thioridazine}} | Drugs.com = {{drugs.com|ppa|thioridazine}}
| MedlinePlus = a682119 | MedlinePlus = a682119
| DailyMedID = Thioridazine
| pregnancy_category = Only if clearly needed
| licence_US = Thioridazine
| legal_status = RX-only-medication, non-narcotic
| pregnancy_AU = C
| routes_of_administration = oral (tablets, concentration, sometimes syrup)
| pregnancy_US = N
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_NZ = <!-- Class A, B, C -->
| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
| legal_EU =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_status = Withdrawn by the manufacturer worldwide;<ref name = NHS/> generic formulations are still available by prescription
| routes_of_administration = Oral
| class = ]


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = incomplete | bioavailability = Incomplete
| metabolism = hepatic | metabolism = Hepatic (at least partly mediated by ])
| elimination_half-life = 21–24 hours<ref>{{cite journal | vauthors = Shvartsburd A, Sajadi C, Morton V, Mirabi M, Gordon J, Smith RC | title = Blood levels of haloperidol and thioridazine during maintenance neuroleptic treatment of schizophrenic outpatients | journal = Journal of Clinical Psychopharmacology | volume = 4 | issue = 4 | pages = 194–198 | date = August 1984 | pmid = 6470190 | doi = 10.1097/00004714-198408000-00004 | s2cid = 33161119 }}</ref>
| elimination_half-life = 7–13 hours (up to 20 hours)
| excretion = feces | excretion = Feces


<!--Identifiers--> <!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 50-52-2 | CAS_number = 50-52-2
Line 28: Line 43:
| ATC_suffix = AC02 | ATC_suffix = AC02
| PubChem = 5452 | PubChem = 5452
| PubChemSubstance = 148555
| IUPHAR_ligand = 100 | IUPHAR_ligand = 100
| DrugBank_Ref = {{drugbankcite|changed|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00679 | DrugBank = DB00679
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
Line 37: Line 53:
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00373 | KEGG = D00373
| ChEBI_Ref = {{ebicite|changed|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9566 | ChEBI = 9566
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 479 | ChEMBL = 479
| synonyms =


<!--Chemical data--> <!--Chemical data-->
| C=21 | H=26 | N=2 | S=2 | C=21 | H=26 | N=2 | S=2
| SMILES = S(c2cc1N(c3c(Sc1cc2)cccc3)CCC4N(C)CCCC4)C
| molecular_weight = 370.577
| smiles = S(c2cc1N(c3c(Sc1cc2)cccc3)CCC4N(C)CCCC4)C
| InChI = 1/C21H26N2S2/c1-22-13-6-5-7-16(22)12-14-23-18-8-3-4-9-20(18)25-21-11-10-17(24-2)15-19(21)23/h3-4,8-11,15-16H,5-7,12-14H2,1-2H3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C21H26N2S2/c1-22-13-6-5-7-16(22)12-14-23-18-8-3-4-9-20(18)25-21-11-10-17(24-2)15-19(21)23/h3-4,8-11,15-16H,5-7,12-14H2,1-2H3 | StdInChI = 1S/C21H26N2S2/c1-22-13-6-5-7-16(22)12-14-23-18-8-3-4-9-20(18)25-21-11-10-17(24-2)15-19(21)23/h3-4,8-11,15-16H,5-7,12-14H2,1-2H3
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}} }}


'''Thioridazine''' ('''Melleril''', '''Novoridazine''', '''Thioril''') is a ] typical (but see next paragraph, below) ] ] belonging to the ] drug group and was previously widely used in the treatment of ] and ]. Due to concerns about ] and ] at high doses this drug is not commonly prescribed, reserved for patients who have failed to respond to, or have contraindications for, more widely used antipsychotics. A serious side effect is the potentially fatal ]. It exerts its actions through a central adrenergic-blocking, a ]-blocking, and minor ] activity. '''Thioridazine''' ('''Mellaril''' or '''Melleril''') is a first generation ] ] belonging to the ] drug group and was previously widely used in the treatment of ] and ]. The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.<ref name = NHS/>

In older references, it is sometimes described as ],<ref name="pmid6540455">{{cite journal |author=Robertson A, MacDonald C |title=Atypical neuroleptics clozapine and thioridazine enhance amphetamine-induced stereotypy |journal=Pharmacol. Biochem. Behav. |volume=21 |issue=1 |pages=97–101 |year=1984 |month=July |pmid=6540455 |doi= 10.1016/0091-3057(84)90137-0|url=}}</ref> but more recently it is usually described as ],<ref name="pmid11850147">{{cite journal |author=Ichikawa J, Dai J, O'Laughlin IA, Fowler WL, Meltzer HY |title=Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum |journal=Neuropsychopharmacology |volume=26 |issue=3 |pages=325–39 |year=2002 |month=March |pmid=11850147 |doi=10.1016/S0893-133X(01)00312-8}}</ref> with the term "atypical" usually reserved for agents showing ] selectivity or ].


==Indications== ==Indications==
Thioridazine was voluntarily discontinued by its manufacturer, ], worldwide because it caused severe cardiac arrhythmias. However, generics remain on the market in some countries.<ref name=NHS>{{cite web|title=SHARED CARE PROTOCOL Thioridazine|work=NHS Lothian Joint Formulary|date=March 2012|url=http://www.ljf.scot.nhs.uk/SharedCareofMedicines/Shared%20Care%20Agreements/SCA/SCA%20Thioridazine%20v1%200%20Final.pdf|url-status=dead|archive-url=https://web.archive.org/web/20150518080549/http://www.ljf.scot.nhs.uk/SharedCareofMedicines/Shared%20Care%20Agreements/SCA/SCA%20Thioridazine%20v1%200%20Final.pdf|archive-date=18 May 2015}}</ref><ref name=PDS2012>{{cite journal | vauthors = Purhonen M, Koponen H, Tiihonen J, Tanskanen A | title = Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort | journal = Pharmacoepidemiology and Drug Safety | volume = 21 | issue = 11 | pages = 1227–1231 | date = November 2012 | pmid = 22941581 | doi = 10.1002/pds.3346 | s2cid = 19560432 }}</ref><ref>{{cite news|title=WHO Pharmaceuticals Newsletter 2005, No. 04: REGULATORY MATTERS: Thioridazine - Sale discontinued in Canada|date=2005|work=Essential Medicines and Health Products Information Portal|publisher=World Health Organization|url=http://apps.who.int/medicinedocs/en/d/Js8119e/1.12.html|archive-url=https://web.archive.org/web/20110528180405/http://apps.who.int/medicinedocs/en/d/Js8119e/1.12.html|url-status=dead|archive-date=28 May 2011|access-date=28 October 2013|volume=4|issue=2|page=5}}</ref><ref>{{cite magazine|title=Withdrawal of thioridazine|journal=Australian Prescriber|volume=30|issue=3|page=82|url=http://www.australianprescriber.com/magazine/30/3/article/891.pdf|archive-url=https://web.archive.org/web/20130723103135/http://www.australianprescriber.com/magazine/30/3/article/891.pdf|url-status=usurped|archive-date=23 July 2013|date=June 2007}}</ref>
Previous additional indications were ], ] and ] linked to ] and ] of ] patients. It was even indicated in Europe for the treatment of psychosis in children and adolescents as Melleretten (10&nbsp;mg to 60&nbsp;mg daily).


Its primary use in medicine is for the treatment of schizophrenia.<ref name = GG>{{cite book | veditors = Brunton LL, Chabner B, Knollmann BC |title=Goodman & Gilman's The Pharmacological Basis of Therapeutics |edition=12th |location=New York |publisher=McGraw-Hill |year=2011 |isbn=978-0-07-162442-8|title-link=Goodman & Gilman's The Pharmacological Basis of Therapeutics }}</ref> It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia,<ref>{{cite journal | vauthors = Kirchner V, Kelly CA, Harvey RJ | title = Thioridazine for dementia | journal = The Cochrane Database of Systematic Reviews | issue = 3 | pages = CD000464 | date = 2001 | pmid = 11686961 | pmc = 7034526 | doi = 10.1002/14651858.CD000464 }}</ref> but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended.<ref>{{cite journal | vauthors = Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AI, van Driel ML, Christiaens T | title = Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 3 | pages = CD007726 | date = March 2013 | pmid = 23543555 | doi = 10.1002/14651858.CD007726.pub2 | hdl-access = free | hdl = 1854/LU-3109108 }}</ref>
It was also given off-label for the treatment of ] and for alleviation of ] withdrawal. {{Citation needed|date=July 2008}}
Generic forms of thioridazine remain on the market in a few countries, usually with restrictions due to the risk of arrhythmias. For example, in the US, it is restricted to patients who have taken at least 2 other antipsychotics that either failed or caused serious side effects.<ref name="medlineplus.gov">{{cite web |title=Thioridazine: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a682119.html |website=medlineplus.gov |access-date=7 June 2023 |language=en}}</ref>

Thioridazine is known to kill multidrug-resistant '']'' and ] at clinical concentrations.<ref>Amaral L, Viveiros M, Molnar J. "Antimicrobial activity of phenothiazines."</ref><ref>{{cite journal |author=Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D |title=Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now! |journal=Int. J. Antimicrob. Agents |volume=35 |issue=6 |pages=524–6 |year=2010 |month=June |pmid=20188526 |doi=10.1016/j.ijantimicag.2009.12.019 |url=}}</ref>

==Metabolism==
Thioridazine is a ] compound with two ]s, both of which are metabolized, according to Eap et al., by ] into (S)- and (R)-thioridazine 2-sulfoxide, better known as ],<ref> National Center for Biotechnology Information.</ref> and into (S)- and (R)-thioridazine-5-sulfoxide.<ref>Eap CB, Guentert TW, Schaublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P. "Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin." ''Clinical Pharmacology & Therapy.'' 1996 Mar;59(3):322–31. PMID 8653995</ref> Mesoridazine is in turn metabolized into ].<ref> National Center for Biotechnology Information.</ref> Thioridazine is an inhibitor of ] and CYP3A2.<ref>Daniel WA, Syrek M, Rylko Z, Kot M. "Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver." ''Polish Journal of Pharmacology.'' 2001 Nov-Dec;53(6):615–21. PMID 11985335 (PDF)</ref>


==Side effects== ==Side effects==
For further information see: ] {{further information|Phenothiazine}}


Thioridazine prolongs the ] in a dose-dependent manner.<ref name = DM>{{cite web|title=THIORIDAZINE HYDROCHLORIDE tablet, film coated |work=DailyMed|publisher=Mutual Pharmaceutical|date=September 2010|access-date=28 October 2013|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9c4bedb4-2d59-4fcd-aad7-fce988cd96d8}}</ref> It produces significantly less ] than most first-generation antipsychotics, likely due to its potent anticholinergic effect.<ref>{{cite journal | vauthors = Fenton M, Rathbone J, Reilly J, Sultana A | title = Thioridazine for schizophrenia | journal = The Cochrane Database of Systematic Reviews | volume = 2007 | issue = 3 | pages = CD001944 | date = July 2007 | pmid = 17636691 | pmc = 6718212 | doi = 10.1002/14651858.CD001944.pub2 }}</ref><ref>{{cite journal | vauthors = Keks N, McGrath J, Lambert T, Catts S, Vaddadi K, Burrows G, Varghese F, George T, Hustig H, Burnett P | display-authors = 6 | title = The Australian multicentre double-blind comparative study of remoxipride and thioridazine in schizophrenia | journal = Acta Psychiatrica Scandinavica | volume = 90 | issue = 5 | pages = 358–365 | date = November 1994 | pmid = 7872041 | doi = 10.1111/j.1600-0447.1994.tb01607.x | s2cid = 40042606 }}</ref> Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies (specifically retinitis pigmentosa).<ref>{{cite journal | vauthors = Fornaro P, Calabria G, Corallo G, Picotti GB | title = Pathogenesis of degenerative retinopathies induced by thioridazine and other antipsychotics: a dopamine hypothesis | journal = Documenta Ophthalmologica. Advances in Ophthalmology | volume = 105 | issue = 1 | pages = 41–49 | date = July 2002 | pmid = 12152801 | doi = 10.1023/A:1015768114192 | s2cid = 23618581 }}</ref> It has a higher propensity for causing ] side effects coupled with a lower propensity for causing ] and sedation than ], but also has a higher incidence of hypotension and cardiotoxicity.<ref>{{cite web|title=Martindale: The Complete Drug Reference|date=18 August 2010|access-date=28 October 2013|work=Medicines Complete|publisher=The Pharmaceutical Press|url=https://www.medicinescomplete.com/mc/martindale/current/login.htm?uri=http%3A%2F%2Fwww.medicinescomplete.com%2Fmc%2Fmartindale%2Fcurrent%2F}}</ref> It is also known to possess a relatively high liability for causing ] compared to other antipsychotics. Similarly to other first-generation antipsychotics it has a relatively high liability for causing prolactin elevation. It is moderate risk for causing weight gain.<ref name = UpToDate>{{cite web|title=Selected adverse effects of antipsychotic medications for schizophrenia|work=UpToDate|publisher=Wolters Kluwer Health|access-date=24 October 2013|url=http://www.uptodate.com/contents/pharmacotherapy-for-schizophrenia-side-effect-management?detectedLanguage=en&source=search_result&search=Selected+adverse+effects+of+antipsychotic+medications+for+schizophrenia&selectedTitle=1%7E150&provider=noProvider#subscribeMessage}}</ref> As with all antipsychotics thioridazine has been linked to cases of ] (an often permanent neurological disorder characterised by slow, repetitive, purposeless and involuntary movements, most often of the facial muscles, that is usually brought on by years of continued treatment with antipsychotics, especially the first-generation (or ''typical'') antipsychotics such as thioridazine) and ] (a potentially fatal complication of antipsychotic treatment).<ref name = DM/> Blood dyscrasias such as ], ] and ] are possible with thioridazine treatment.<ref name = DM/> Thioridazine is also associated with abnormal retinal pigmentation after many years of use.<ref>{{cite journal | vauthors = Scott AW | title = Retinal Pigmentation in a Patient Receiving Thioridazine | journal = Archives of Ophthalmology | volume = 70 | issue = 6 | pages = 775–778 | date = December 1963 | pmid = 14065014 | doi = 10.1001/archopht.1963.00960050777009 }}</ref>
The most commonly complained about side effect is ] which is the main reason for low patient compliance
Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.<ref>{{Cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/n/livertox/Thioridazine/|title=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury|chapter=Thioridazine|year=2012|publisher=National Institute of Diabetes and Digestive and Kidney Diseases|pmid=31643669 }}</ref>


==Pharmacology==
] characterized by involuntary movements of the lips, mouth, and tongue can be long lasting or irreversible, tremor of the mouth and lips without tongue involvement constitutes ]. ] is potentially fatal.


Thioridazine has the following binding profile:<ref>{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP)|author1-link=Bryan Roth | vauthors = Roth BL, Driscol J | url = http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 28 October 2013 | date = 12 January 2011 | url-status = dead | archive-url = https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php | archive-date = 8 November 2013}}</ref>
Central nervous system side effects occur. These are mainly drowsiness, dizziness, fatigue, and vertigo. Early and late ] side effects are seen only infrequently (less than 1% altogether). There is no clear dose-effect relationship, as with higher doses anticholinergic effects of thioridazine become more prominent.
{| class="wikitable"
|-
! Biologic Protein !! Binding affinity (K<sub>i</sub>) !! Binding affinity of ] (K<sub>i</sub> ) !! Binding affinity of ] (K<sub>i</sub> ) !! Notes
|-
| ] || 1259 || ND || ND ||
|-
| ] || 842 || ND || ND ||
|-
| ] || 1684 || ND || ND ||
|-
| ] || 144.35 || 500 (HB) || ND ||
|-
| ] || 109 || ND || ND ||
|-
| ] || 579 || ND|| ND ||
|-
| ] || 194 || ND || ND ||
|-
| ] || 27.67 || 4.76 (HB)|| ND || The ratio of 5-HT2A to D2 receptor binding is believed to dictate whether or not most antipsychotics are ] or ]. In thioridazine's case its ratio of 5-HT2A to D2 receptor binding is below the level that's believed to be required for ''atypicality'' despite its relatively low extrapyramidal side effect liability in practice.<ref name = GG/>
|-
| ] || 53 || 157 || ND || Believed to play a role in the weight gain-promoting effects of antipsychotics.<ref name = GG/>
|-
| ] || >10000 || ND || ND ||
|-
| ] || 364 || ND || ND ||
|-
| ] || 57.05 || 380 || ND ||
|-
| ] || 99 || 73 (RC) || ND ||
|-
| ] || 3.15 || 2 (HB) || ND || Likely the receptor responsible for the ] known to occur in individuals on thioridazine.<ref name = GG/>
|-
| ] || 2.4 || ND || ND ||
|-
| ] || 134.15 || 1612.9 (HB) || ND ||
|-
| ] || 341.65 || ND || ND ||
|-
| ] || 74.9 || ND || ND ||
|-
| ] || >10000 || ND || ND ||
|-
| ] || >10000 || ND || ND ||
|-
| ] || 12.8 || 10 || ND || This receptor is believed to be the chief receptor responsible for the ] side effects of thioridazine (e.g. dry mouth, constipation, blurred vision, etc.). Likely plays a role in thioridazine's low extrapyramidal side effect liability as anticholinergic drugs such as ] are routinely given to treat ] resulting from antipsychotic treatment.<ref name = GG/>
|-
| ] || 286.33 || 15 || ND ||
|-
| ] || 29 || 90 || ND ||
|-
| ] || 310.33 || 19 || ND ||
|-
| ] || 12.67 || 60 || ND ||
|-
| ] || 94.5 || ND || ND ||
|-
| ] || 0.4 || 4.3 || 0.25 || Believed to be the receptor responsible for the therapeutic effects of antipsychotics.<ref name = GG/>
|-
| ] || 1.5 || 2.6 || 0.7 ||
|-
| ] || 1.5 || 9.1 || ND ||
|-
| ] || 258 || ND || ND ||
|-
| ] || 191 || ND|| ND || Likely involved in thioridazine's cardiac effects.
|-
| ] || 16.5 || 1.81 (HB) || ND || Likely responsible for the sedating effects of thioridazine.
|-
| ] || 136 || ND || ND || Regulates the release of ] into the ].
|-
| ] || 2400 || ND || ND ||
|}


''Note: The Binding affinities given are towards cloned human receptors unless otherwise specified''
Thioridazine causes also an unusual high incidence of ] and ] due to a strong ] activity. Painful ejaculation or no ejaculation at all is also sometimes seen.{{Citation needed|date=July 2008}}


'''Acronyms used'''<br>
Autonomous side effects (], ] difficulty, ], induction of ], ], and ]) occur obviously less often than with most other mildly potent antipsychotics.
HB – Human brain receptor<br>
RC – Cloned rat receptor<br>
ND – No data


==Metabolism==
Thioridazine is no longer recommended as first-line treatment due its side effect of prolonging the ] on the ]. Thioridazine-5-sulfoxide is associated with ] and ].<ref>Heath A, Svensson C, Martensson E. "Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose." ''Veterinary and Human Toxicology.'' 1985 Apr;27(2):100–5. PMID 3992882</ref>
Thioridazine is a ] compound with two ]s, both of which are metabolized, according to Eap et al., by ] into (''S'')- and (''R'')-thioridazine-2-sulfoxide, better known as ],<ref> National Center for Biotechnology Information.</ref> and into (''S'')- and (''R'')-thioridazine-5-sulfoxide.<ref>{{cite journal | vauthors = Eap CB, Guentert TW, Schãublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P | title = Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin | journal = Clinical Pharmacology and Therapeutics | volume = 59 | issue = 3 | pages = 322–331 | date = March 1996 | pmid = 8653995 | doi = 10.1016/S0009-9236(96)80010-5 | s2cid = 45135063 }}</ref> Mesoridazine is in turn metabolized into ].<ref> National Center for Biotechnology Information.</ref> Thioridazine is an inhibitor of ] and CYP3A4.<ref>{{cite journal | vauthors = Daniel WA, Syrek M, Ryłko Z, Kot M | title = Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver | journal = Polish Journal of Pharmacology | volume = 53 | issue = 6 | pages = 615–621 | year = 2001 | pmid = 11985335 | url = http://www.if-pan.krakow.pl/pjp/pdf/2001/6_615.pdf }}</ref>


==History==
It can also cause ], which is more common in older individuals.<ref>p229, Robbins and Cotran ''Review of Pathology'', 3rd edition, Klatt and Kumar</ref>
The manufacturer ]/Sandoz/Wander of the brands of thioridazine, Mellaril in the US and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.<ref name = NHS/><ref name=PDS2012/>


Generic forms of thioridazine however remain on the market in a few countries usually with restrictions for example in the US its restricted to patients who have taken at least 2 other antipsychotics that either failed or caused serious side effects <ref name="medlineplus.gov"/>
Also, the serious and sometimes fatal blood damage ] is seen more frequently (approximately 1/500 to 1/1,000 patients) with thioridazine than with other typical phenothiazines (1/2,000 to 1/10,000 patients).


==Antibiotic activity==
Thioridazine if given over a prolonged time and in high doses can be stored in the ocula and the ] of the eyes and in the heart muscle. Clinical consequences (disturbed or blurred vision) are rare although chromatopsia has been reported.<ref>AJ Giannini, PJ Mahar. An unusual ocular complication of thioridazine. International Journal of Psychiatry in Medicine. 10:217-219, 1980.</ref> {{Citation needed|date=October 2008}}


Thioridazine is known to kill ]<ref>{{cite journal | vauthors = Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D | title = Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now! | journal = International Journal of Antimicrobial Agents | volume = 35 | issue = 6 | pages = 524–526 | date = June 2010 | pmid = 20188526 | doi = 10.1016/j.ijantimicag.2009.12.019 | url = https://hal.archives-ouvertes.fr/hal-00585817/file/PEER_stage2_10.1016%252Fj.ijantimicag.2009.12.019.pdf }}</ref><ref name = XDR>{{cite journal | vauthors = Amaral L, Viveiros M | title = Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections | journal = International Journal of Antimicrobial Agents | volume = 39 | issue = 5 | pages = 376–380 | date = May 2012 | pmid = 22445204 | doi = 10.1016/j.ijantimicag.2012.01.012 }}</ref> and to make ] '']'' sensitive to ].<ref>{{cite journal | vauthors = Thanacoody HK | title = Thioridazine: resurrection as an antimicrobial agent? | journal = British Journal of Clinical Pharmacology | volume = 64 | issue = 5 | pages = 566–574 | date = November 2007 | pmid = 17764469 | pmc = 2203271 | doi = 10.1111/j.1365-2125.2007.03021.x }}</ref><ref>{{cite journal | vauthors = Thorsing M, Klitgaard JK, Atilano ML, Skov MN, Kolmos HJ, Filipe SR, Kallipolitis BH | title = Thioridazine induces major changes in global gene expression and cell wall composition in methicillin-resistant Staphylococcus aureus USA300 | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e64518 | date = May 2013 | pmid = 23691239 | pmc = 3656896 | doi = 10.1371/journal.pone.0064518 | doi-access = free | bibcode = 2013PLoSO...864518T }}</ref> A possible mechanism of action for the drug's antibiotic activity is via the inhibition of ]. The β-lactam antibiotic resistance is due to the secretion ] a protein that destroys antibiotics. If the bacteria cannot secrete the β-lactamase, then the antibiotic will be effective.<ref name = XDR/> The drug has been successfully used in the treatment of ] in conjunction with more conventional ].
==Discontinuation==
It is advisable to withdraw thioridazine gradually and not abruptly to avoid unpleasant withdrawal symptoms (], insomnia, anxiety). Another neuroleptic may be introduced to the therapeutic regime step by step (overlapping), if needed. If sudden withdrawal of thioridazine is necessary, withdrawal symptoms can also be alleviated with the ]s ] (Ativan) 1&nbsp;mg—2&nbsp;mg, ] (Xanax) 0,5&nbsp;mg prn or ] (Klonopin, Rivotril) 0,5&nbsp;mg to 2&nbsp;mg prn (as needed)or ] (Valium)5 – 10&nbsp;mg prn for up to 2 weeks (not longer to avoid addiction). {{Citation needed|date=July 2008}}


==History== ==Synthesis==
Note: Same sidechain used for ] and ].
The manufacturer ]/Sandoz/Wander of the brands of thioridazine, Mellaril in the USA and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.
Synthesis:<ref>{{cite journal | vauthors = Bourquin JP, Schwarb G, Gamboni G, Fischer R, Ruesch L, Guldimann S, Theus V, Schenker E, Renz J | date = 1958 | title = Synthesen auf dem Phenothiazin-Gebiet. 2. Mitteilung. N-substituierte Mercaptophenothiazin-Derivate | journal = Helvetica Chimica Acta | volume = 41 | issue = 4 | pages = 1072–1108 | doi = 10.1002/hlca.19580410420 }}</ref> Patent:<ref>{{cite patent | inventor = Renz J, Bourquin JP | title = Phenothiazine derivatives substituted by a monovalent sulfur function in 3-position | url = https://patents.google.com/patent/US3239514A/en?oq=US+3239514 | country = US | number = 3239514 | gdate = 1966 | assign1 = Sandoz KK }}</ref> Sidechain:<ref name="pmid20994984">{{cite journal | vauthors = Norton TR, Seibert RA, Benson AA, Bergstrom FW | title = The synthesis of some substituted 8-aminoquinolines | journal = Journal of the American Chemical Society | volume = 68 | issue = 8| pages = 1572–6 | date = August 1946 | pmid = 20994984 | doi = 10.1021/ja01212a058 | bibcode = 1946JAChS..68.1572N }}</ref> Enantiomers:<ref>{{cite journal | vauthors = Antonsen SG, Monsen EB, Ovchinnikov K, Nolsøe JM, Ekeberg D, Kristiansen JE, Diep DB, Stenstrøm YH | title = Synthesis of the enantiomers of thioridazine. | journal = SynOpen | date = 2020 | volume = 4 | issue = 1 | pages = 12–16 | doi = 10.1055/s-0039-1690834 | doi-access = free }}</ref>]]
The alkylation of 2-Picoline ('''1''') with formaldehyde gives 2-Pyridineethanol ('''2'''). Forming the quat salt with methyl iodide leads to 2-(2-hydroxyethyl)-1-methyl-pyridinium iodide ('''3'''). Catalytic hydrogenation in the presence of hydrochloric acid leads to 2-(2-Chloroethyl)-1-Methylpiperidine ('''4'''). Alkylation of 2-Methylthiophenothiazine ('''5''') in the presence of sodium hydride base completed the synthesis of ''Thioridazine'' ('''6''').


== References ==
The usual dosage was 50&nbsp;mg per day for mild cases to 600–800&nbsp;mg per day for severely disturbed patients.
{{Reflist}}


== Further reading ==
Thioridazine may still be available from other manufacturers as a generic drug with the precaution that it is used only in psychotic patients refractory to other forms of drug treatment. ECG-monitoring and frequent ] counts are required before initiating therapy and in close intervals afterwards.
{{refbegin}}

* {{cite book | vauthors = Dean L | chapter=Thioridazine Therapy and CYP2D6 Genotypes | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK424018/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | title=Medical Genetics Summaries | publisher=] (NCBI) | year=2017 | pmid=28520378 | id=Bookshelf ID: NBK424018 | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}
A multi-year UK study by the Alzheimer's Research Trust suggested that this and other ] ] drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse. {{Citation needed|date=July 2008}}<ref>
{{refend}}
{{cite news |first= |last=
|authorlink=
|author=
|coauthors=
|title=Medication 'worsens Alzheimer's' |url=http://news.bbc.co.uk/1/hi/health/7319393.stm
|format=
|work= |publisher=BBC News
|location= |id= |pages= |page= |date= 1 April 2008
|accessdate=2008-04-01
|language=
|quote=Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills.
|archiveurl=
|archivedate=
}}</ref> The study concluded that {{cquote|For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status and by some measures improved functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this possibility must be weighed against the unwanted effects of therapy. The current study helps to inform a clinical management strategy for current practice, but the considerable risks of maintenance therapy highlight the urgency of further work to find, develop, and implement safer and more effective treatment approaches for neuropsychiatric symptoms in people with AD.}}
<ref>{{cite journal
|journal=PLOS Medicine
|title=A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)
|author=Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, et al.
|volume=5 |issue=4, e76
|doi=10.1371/journal.pmed.0050076
|year=2008
|pages=e76
|pmid=18384230
|pmc=2276521
|editor1-last=Brayne
|editor1-first=Carol
}}</ref>
{{Expand section|date=June 2008}}
==Chemistry==
Thioridazine, (10--2-(methylthio)phenothiazine) is synthesized by alkylating 2-methylthiophenothiazine with 2-(2-chloroethyl)-1-methylpiperidine.
]
*J. Renz, J.P. Bourquin, G. Gamboni, G. Schwarb, {{US Patent|3239514}} (1966).
*{{Cite doi|10.1002/hlca.19580410420}}
== References ==
{{Reflist|2}}


== External links == == External links ==
* National Center for Biotechnology Information,. * {{cite web| url = https://druginfo.nlm.nih.gov/drugportal/name/thioridazine | publisher = U.S. National Library of Medicine| work = Drug Information Portal | title = Thioridazine }}
* ''Schizophrenia Daily News Blog.'' * ''Schizophrenia Daily News Blog.''
*


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Latest revision as of 07:17, 21 December 2024

Typical antipsychotic medication "Aldazine" redirects here. For functional group, see Aldazines. Not to be confused with Thorazine.
This article's lead section may be too short to adequately summarize the key points. Please consider expanding the lead to provide an accessible overview of all important aspects of the article. (September 2021)

Pharmaceutical compound
Thioridazine
Clinical data
AHFS/Drugs.comProfessional Drug Facts
MedlinePlusa682119
License data
Pregnancy
category
  • AU: C
Routes of
administration		Oral
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances)
  • Withdrawn by the manufacturer worldwide; generic formulations are still available by prescription
Pharmacokinetic data
BioavailabilityIncomplete
MetabolismHepatic (at least partly mediated by CYP2D6)
Elimination half-life21–24 hours
ExcretionFeces
Identifiers
IUPAC name
  • 10-{2-ethyl}-
    2-methylsulfanylphenothiazine
CAS Number
PubChem CID
PubChem SID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.041 Edit this at Wikidata
Chemical and physical data
FormulaC21H26N2S2
Molar mass370.57 g·mol
3D model (JSmol)
SMILES
  • S(c2cc1N(c3c(Sc1cc2)cccc3)CCC4N(C)CCCC4)C
InChI
  • InChI=1S/C21H26N2S2/c1-22-13-6-5-7-16(22)12-14-23-18-8-3-4-9-20(18)25-21-11-10-17(24-2)15-19(21)23/h3-4,8-11,15-16H,5-7,12-14H2,1-2H3
  • Key:KLBQZWRITKRQQV-UHFFFAOYSA-N
  (verify)

Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.

Indications

Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias. However, generics remain on the market in some countries.

Its primary use in medicine is for the treatment of schizophrenia. It was also tried with some success as a treatment for various psychiatric symptoms seen in people with dementia, but chronic use of thioridazine and other anti-psychotics in people with dementia is not recommended. Generic forms of thioridazine remain on the market in a few countries, usually with restrictions due to the risk of arrhythmias. For example, in the US, it is restricted to patients who have taken at least 2 other antipsychotics that either failed or caused serious side effects.

Side effects

Further information: Phenothiazine

Thioridazine prolongs the QTc interval in a dose-dependent manner. It produces significantly less extrapyramidal side effects than most first-generation antipsychotics, likely due to its potent anticholinergic effect. Its use, along with the use of other typical antipsychotics, has been associated with degenerative retinopathies (specifically retinitis pigmentosa). It has a higher propensity for causing anticholinergic side effects coupled with a lower propensity for causing extrapyramidal side effects and sedation than chlorpromazine, but also has a higher incidence of hypotension and cardiotoxicity. It is also known to possess a relatively high liability for causing orthostatic hypotension compared to other antipsychotics. Similarly to other first-generation antipsychotics it has a relatively high liability for causing prolactin elevation. It is moderate risk for causing weight gain. As with all antipsychotics thioridazine has been linked to cases of tardive dyskinesia (an often permanent neurological disorder characterised by slow, repetitive, purposeless and involuntary movements, most often of the facial muscles, that is usually brought on by years of continued treatment with antipsychotics, especially the first-generation (or typical) antipsychotics such as thioridazine) and neuroleptic malignant syndrome (a potentially fatal complication of antipsychotic treatment). Blood dyscrasias such as agranulocytosis, leukopenia and neutropenia are possible with thioridazine treatment. Thioridazine is also associated with abnormal retinal pigmentation after many years of use. Thioridazine has been correlated to rare instances of clinically apparent acute cholestatic liver injury.

Pharmacology

Thioridazine has the following binding profile:

Biologic Protein Binding affinity (Ki) Binding affinity of Mesoridazine (Ki ) Binding affinity of Sulforidazine (Ki ) Notes
SERT 1259 ND ND
NET 842 ND ND
DAT 1684 ND ND
5-HT1A 144.35 500 (HB) ND
5-HT1B 109 ND ND
5-HT1D 579 ND ND
5-HT1E 194 ND ND
5-HT2A 27.67 4.76 (HB) ND The ratio of 5-HT2A to D2 receptor binding is believed to dictate whether or not most antipsychotics are atypical or typical. In thioridazine's case its ratio of 5-HT2A to D2 receptor binding is below the level that's believed to be required for atypicality despite its relatively low extrapyramidal side effect liability in practice.
5-HT2C 53 157 ND Believed to play a role in the weight gain-promoting effects of antipsychotics.
5-HT3 >10000 ND ND
5-HT5A 364 ND ND
5-HT6 57.05 380 ND
5-HT7 99 73 (RC) ND
α1A 3.15 2 (HB) ND Likely the receptor responsible for the orthostatic hypotension known to occur in individuals on thioridazine.
α1B 2.4 ND ND
α2A 134.15 1612.9 (HB) ND
α2B 341.65 ND ND
α2C 74.9 ND ND
β1 >10000 ND ND
β2 >10000 ND ND
M1 12.8 10 ND This receptor is believed to be the chief receptor responsible for the anticholinergic side effects of thioridazine (e.g. dry mouth, constipation, blurred vision, etc.). Likely plays a role in thioridazine's low extrapyramidal side effect liability as anticholinergic drugs such as benzatropine are routinely given to treat extrapyramidal side effects resulting from antipsychotic treatment.
M2 286.33 15 ND
M3 29 90 ND
M4 310.33 19 ND
M5 12.67 60 ND
D1 94.5 ND ND
D2 0.4 4.3 0.25 Believed to be the receptor responsible for the therapeutic effects of antipsychotics.
D3 1.5 2.6 0.7
D4 1.5 9.1 ND
D5 258 ND ND
hERG 191 ND ND Likely involved in thioridazine's cardiac effects.
H1 16.5 1.81 (HB) ND Likely responsible for the sedating effects of thioridazine.
H2 136 ND ND Regulates the release of hydrochloric acid into the stomach.
H4 2400 ND ND

Note: The Binding affinities given are towards cloned human receptors unless otherwise specified

Acronyms used
HB – Human brain receptor
RC – Cloned rat receptor
ND – No data

Metabolism

Thioridazine is a racemic compound with two enantiomers, both of which are metabolized, according to Eap et al., by CYP2D6 into (S)- and (R)-thioridazine-2-sulfoxide, better known as mesoridazine, and into (S)- and (R)-thioridazine-5-sulfoxide. Mesoridazine is in turn metabolized into sulforidazine. Thioridazine is an inhibitor of CYP1A2 and CYP3A4.

History

The manufacturer Novartis/Sandoz/Wander of the brands of thioridazine, Mellaril in the US and Canada and Melleril in Europe, discontinued the drug worldwide in June 2005.

Generic forms of thioridazine however remain on the market in a few countries usually with restrictions for example in the US its restricted to patients who have taken at least 2 other antipsychotics that either failed or caused serious side effects

Antibiotic activity

Thioridazine is known to kill extensively drug-resistant tuberculosis and to make methicillin-resistant Staphylococcus aureus sensitive to β-lactam antibiotics. A possible mechanism of action for the drug's antibiotic activity is via the inhibition of bacterial secretion pumps. The β-lactam antibiotic resistance is due to the secretion β-lactamase a protein that destroys antibiotics. If the bacteria cannot secrete the β-lactamase, then the antibiotic will be effective. The drug has been successfully used in the treatment of granulomatous amoebic encephalitis in conjunction with more conventional amoebicidal medications.

Synthesis

Note: Same sidechain used for mesoridazine and sulforidazine.

Thieme Synthesis: Patent: Sidechain: Enantiomers:

The alkylation of 2-Picoline (1) with formaldehyde gives 2-Pyridineethanol (2). Forming the quat salt with methyl iodide leads to 2-(2-hydroxyethyl)-1-methyl-pyridinium iodide (3). Catalytic hydrogenation in the presence of hydrochloric acid leads to 2-(2-Chloroethyl)-1-Methylpiperidine (4). Alkylation of 2-Methylthiophenothiazine (5) in the presence of sodium hydride base completed the synthesis of Thioridazine (6).

References

  1. Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  2. ^ "SHARED CARE PROTOCOL Thioridazine" (PDF). NHS Lothian Joint Formulary. March 2012. Archived from the original (PDF) on 18 May 2015.
  3. Shvartsburd A, Sajadi C, Morton V, Mirabi M, Gordon J, Smith RC (August 1984). "Blood levels of haloperidol and thioridazine during maintenance neuroleptic treatment of schizophrenic outpatients". Journal of Clinical Psychopharmacology. 4 (4): 194–198. doi:10.1097/00004714-198408000-00004. PMID 6470190. S2CID 33161119.
  4. ^ Purhonen M, Koponen H, Tiihonen J, Tanskanen A (November 2012). "Outcome of patients after market withdrawal of thioridazine: a retrospective analysis in a nationwide cohort". Pharmacoepidemiology and Drug Safety. 21 (11): 1227–1231. doi:10.1002/pds.3346. PMID 22941581. S2CID 19560432.
  5. "WHO Pharmaceuticals Newsletter 2005, No. 04: REGULATORY MATTERS: Thioridazine - Sale discontinued in Canada". Essential Medicines and Health Products Information Portal. Vol. 4, no. 2. World Health Organization. 2005. p. 5. Archived from the original on 28 May 2011. Retrieved 28 October 2013.
  6. "Withdrawal of thioridazine" (PDF). Australian Prescriber. Vol. 30, no. 3. June 2007. p. 82. Archived from the original on 23 July 2013.{{cite magazine}}: CS1 maint: unfit URL (link)
  7. ^ Brunton LL, Chabner B, Knollmann BC, eds. (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8.
  8. Kirchner V, Kelly CA, Harvey RJ (2001). "Thioridazine for dementia". The Cochrane Database of Systematic Reviews (3): CD000464. doi:10.1002/14651858.CD000464. PMC 7034526. PMID 11686961.
  9. Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AI, van Driel ML, Christiaens T (March 2013). "Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia". The Cochrane Database of Systematic Reviews. 3 (3): CD007726. doi:10.1002/14651858.CD007726.pub2. hdl:1854/LU-3109108. PMID 23543555.
  10. ^ "Thioridazine: MedlinePlus Drug Information". medlineplus.gov. Retrieved 7 June 2023.
  11. ^ "THIORIDAZINE HYDROCHLORIDE tablet, film coated [Mutual Pharmaceutical]". DailyMed. Mutual Pharmaceutical. September 2010. Retrieved 28 October 2013.
  12. Fenton M, Rathbone J, Reilly J, Sultana A (July 2007). "Thioridazine for schizophrenia". The Cochrane Database of Systematic Reviews. 2007 (3): CD001944. doi:10.1002/14651858.CD001944.pub2. PMC 6718212. PMID 17636691.
  13. Keks N, McGrath J, Lambert T, Catts S, Vaddadi K, Burrows G, et al. (November 1994). "The Australian multicentre double-blind comparative study of remoxipride and thioridazine in schizophrenia". Acta Psychiatrica Scandinavica. 90 (5): 358–365. doi:10.1111/j.1600-0447.1994.tb01607.x. PMID 7872041. S2CID 40042606.
  14. Fornaro P, Calabria G, Corallo G, Picotti GB (July 2002). "Pathogenesis of degenerative retinopathies induced by thioridazine and other antipsychotics: a dopamine hypothesis". Documenta Ophthalmologica. Advances in Ophthalmology. 105 (1): 41–49. doi:10.1023/A:1015768114192. PMID 12152801. S2CID 23618581.
  15. "Martindale: The Complete Drug Reference". Medicines Complete. The Pharmaceutical Press. 18 August 2010. Retrieved 28 October 2013.
  16. "Selected adverse effects of antipsychotic medications for schizophrenia". UpToDate. Wolters Kluwer Health. Retrieved 24 October 2013.
  17. Scott AW (December 1963). "Retinal Pigmentation in a Patient Receiving Thioridazine". Archives of Ophthalmology. 70 (6): 775–778. doi:10.1001/archopht.1963.00960050777009. PMID 14065014.
  18. "Thioridazine". LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases. 2012. PMID 31643669.
  19. Roth BL, Driscol J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 28 October 2013.
  20. PubChem Substance Summary: Mesoridazine National Center for Biotechnology Information.
  21. Eap CB, Guentert TW, Schãublin-Loidl M, Stabl M, Koeb L, Powell K, Baumann P (March 1996). "Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin". Clinical Pharmacology and Therapeutics. 59 (3): 322–331. doi:10.1016/S0009-9236(96)80010-5. PMID 8653995. S2CID 45135063.
  22. PubChem Substance Summary: Sulforidazine National Center for Biotechnology Information.
  23. Daniel WA, Syrek M, Ryłko Z, Kot M (2001). "Effects of phenothiazine neuroleptics on the rate of caffeine demethylation and hydroxylation in the rat liver" (PDF). Polish Journal of Pharmacology. 53 (6): 615–621. PMID 11985335.
  24. Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D (June 2010). "Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now!" (PDF). International Journal of Antimicrobial Agents. 35 (6): 524–526. doi:10.1016/j.ijantimicag.2009.12.019. PMID 20188526.
  25. ^ Amaral L, Viveiros M (May 2012). "Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections". International Journal of Antimicrobial Agents. 39 (5): 376–380. doi:10.1016/j.ijantimicag.2012.01.012. PMID 22445204.
  26. Thanacoody HK (November 2007). "Thioridazine: resurrection as an antimicrobial agent?". British Journal of Clinical Pharmacology. 64 (5): 566–574. doi:10.1111/j.1365-2125.2007.03021.x. PMC 2203271. PMID 17764469.
  27. Thorsing M, Klitgaard JK, Atilano ML, Skov MN, Kolmos HJ, Filipe SR, Kallipolitis BH (May 2013). "Thioridazine induces major changes in global gene expression and cell wall composition in methicillin-resistant Staphylococcus aureus USA300". PLOS ONE. 8 (5): e64518. Bibcode:2013PLoSO...864518T. doi:10.1371/journal.pone.0064518. PMC 3656896. PMID 23691239.
  28. Bourquin JP, Schwarb G, Gamboni G, Fischer R, Ruesch L, Guldimann S, Theus V, Schenker E, Renz J (1958). "Synthesen auf dem Phenothiazin-Gebiet. 2. Mitteilung. N-substituierte Mercaptophenothiazin-Derivate". Helvetica Chimica Acta. 41 (4): 1072–1108. doi:10.1002/hlca.19580410420.
  29. US 3239514, Renz J, Bourquin JP, "Phenothiazine derivatives substituted by a monovalent sulfur function in 3-position", issued 1966, assigned to Sandoz KK 
  30. Norton TR, Seibert RA, Benson AA, Bergstrom FW (August 1946). "The synthesis of some substituted 8-aminoquinolines". Journal of the American Chemical Society. 68 (8): 1572–6. Bibcode:1946JAChS..68.1572N. doi:10.1021/ja01212a058. PMID 20994984.
  31. Antonsen SG, Monsen EB, Ovchinnikov K, Nolsøe JM, Ekeberg D, Kristiansen JE, Diep DB, Stenstrøm YH (2020). "Synthesis of the enantiomers of thioridazine". SynOpen. 4 (1): 12–16. doi:10.1055/s-0039-1690834.

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Antagonists
Precursors
(and prodrugs)
See also
Receptor/signaling modulators
Nicotinic acetylcholine receptor modulators
Acetylcholine metabolism/transport modulators
Serotonin receptor modulators
5-HT1
5-HT1A
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT2
5-HT2A
5-HT2B
5-HT2C
5-HT3–7
5-HT3
5-HT4
5-HT5A
5-HT6
5-HT7
Tricyclics
Classes
Antidepressants
(Tricyclic antidepressants (TCAs))
Antihistamines
Antipsychotics
Anticonvulsants
Anticholinergics
Others
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